The cytotoxic activity of camptothecin is attributable to its ability to interfere with DNA topoisomerase I (Hsiang, Y.-H. et al. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J. Biol. Chem., 260:14873-14878, 1985). DNA topoisomerase I is a phosphorylated protein and is required for DNA replication, transcription and recombination. It forms a covalent reversible DNA topoisomerase I-double strand DNA complex (referred to as cleavable complex) and relaxes supercoiled DNA by cleaving and religating one of the two DNA strands (see for example Wang, J. C. DNA topoisomerases. Annu. Rev. Biochem. 54:665-697, 1985; Champoux, J. J. Mechanistic aspects of type-I topoisomerase. In “DNA topology and its biological effects” pp. 217-242, 1990). Camptothecin reversibly interacts with the cleavable complex and subsequently induces DNA single strand breaks by interfering with the religation step (Hsiang, Y.-H. et al. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J. Biol. Chem., 260:14873-14878, 1985; Porter, S. E. et al. The basis for camptothecin enhancement of DNA breakage by eukaryotic DNA topoisomerase I. Nucleic Acid Res. 17:8521-8532, 1989).
Although DNA topoisomerase I is an ubiquitous enzyme and is present throughout the cell cycle, antiproliferative activities of camptothecin are only limited in clinical trials, and half-life in plasma of camptothecin appeared to be short (less than 30 min) being converted to the inactive carboxylate form. Furthermore, camptothecin is poorly soluble in water, and therefore, it itself can not be formulated for the use of intravenous injection.
A number of camptothecin derivatives were synthesized to improve anti-tumor activity, lactone stability in plasma and/or water solubility, and were tested clinically (Gerrits, C. J. H., de Jonge, M. J. et al. Topoisomerase I inhibitors: the relevance of prolonged exposure for clinical development. Br. J. Cancer, 76: 952-962, 1997; O'Leary, J. et al. Camptothecins: a review of their development and schedules of administration. Eur. J. Cancer, 34: 1500-1508, 1988; Gerderblom, H. A. et al. Oral topoisomerase I inhibitors in adults patients: present and future. Investig. New Drugs, 17: 401-415, 1999).
However, at the present time, only two camptothecin derivatives, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin(irinotecan) that is the prodrug of 7-ethyl-10-hydroxycamptothecin (SN-38, EP 0074256) and 9-(dimethylamino)methyl-10-hydroxycamptothecin(topotecan) have been introduced into clinical practice (Kunimoto, T. et al. Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res., 47:5944-5947, 1987; Kingsbury, W. D. et al. Synthesis of water-soluble (aminoalkyl)camptothecin analogs: inhibition of topoisomerase I and antitumor activity. J. Med. Chem., 34:98-107, 1991).
Due to the structural complexity of camptothecin, there is clearly a limitation of derivatization of camptothecin and synthetic routes preparing them. Thus, there are still strong needs to discover new synthetic routes for delivering new camptothecin analogs with improved activities.